Combined Organ Transplantation

Andrew Malone

General Principles

Kidney failure can occur as a consequence of pathology primary to another vital organ such as the pancreas, liver, or heart. Therefore, frequently both diseased organs are transplanted at the same time.
Pancreas transplantation is a therapeutic option for certain diabetic patients.
Diabetes mellitus type 1 is due to pancreatic endocrine failure resulting in the reduction or loss of insulin secretion from pancreatic beta cells.
Diabetes mellitus type 2 is due to the reduction of insulin sensitivity in the peripheral tissues resulting in the need for increased circulating insulin levels.
Simultaneous kidney and pancreas transplantation is the most common form of pancreas transplantation. Pancreas transplantation after kidney transplant and pancreas transplant alone represents approximately 20% of all pancreas transplantation.¹
The number of combined liver and kidney transplants has been increasing in recent years. In 2017, liver and kidney transplants made up 9.6% of livers transplanted.²
Pancreas transplant function can be compromised for many reasons both immunologic and nonimmunologic.
Pancreas transplant dysfunction occurs more frequently than kidney transplant dysfunction.
Combined heart and kidney transplantation is performed less frequently than kidney-pancreas and kidney-liver transplants.
In total 807 combined heart-kidney transplants have been performed between 1988 and 2012 according to United Network for Organ Sharing (UNOS) and in 2017 combined heart-kidney transplants made up 6.5% of all hearts transplanted.³
There are currently no standardized guidelines or indications for combined heart-kidney transplantation.
Pre-heart transplantation estimated glomerular filtration rate predicts post-heart transplant mortality and progression to end-stage renal disease (ESRD). Hazard ratio for mortality post-heart transplantation is 1.55 (95% CI 1.41–1.70) for eGFR <30 mL/min/1.73 m² by MDRD.⁴
Simultaneous pancreas-kidney (SPK) transplantation is the most common combined transplant performed.
This chapter will focus on SPK transplantation for this reason. The details of induction and maintenance immunosuppression for other combined transplants are beyond the scope of this chapter.

Indications for Pancreas Transplantation

UNOS is a not-for-profit organization charged with overseeing the allocation of organs in the United States.
Indications for pancreas transplantation according to UNOS policy (11.2.A); one of these is required⁵:
- Have a diagnosis of diabetes mellitus
- Have documented pancreatic exocrine deficiency
- Require the procurement or transplantation of a pancreas as part of a multiple organ transplant for technical reasons (e.g., part of a multivisceral abdominal organ transplant—bowel, liver, pancreas)
The American Diabetic Association (ADA) guidelines recommend pancreas transplantation as a therapeutic alternative to insulin in certain circumstances⁶:
- Patients with advanced chronic kidney disease or end-stage kidney disease who are eligible for or have had a kidney transplant
- In the absence of indications for kidney transplantation, pancreas-alone transplantation should only be considered a therapy in patients who fulfill these three criteria:
  - History of frequent, acute, and severe metabolic complications such as hypoglycemia, marked hyperglycemia, or ketoacidosis that have required medical attention;
  - Clinical and emotional problems related to exogenous insulin use that are severe and incapacitating; and
  - Consistent failure of insulin-based management to prevent acute complications.

Risks and Benefits

For each patient an assessment of the short- and long-term risk/benefit ratio must be considered before perusing pancreas transplantation.
Simultaneous kidney-pancreas transplantation offers a survival benefit greater than deceased kidney transplant alone or remaining on dialysis in type 1 diabetic patients.
Pancreas transplantation alone can reverse diabetic nephropathy changes after 5 years of successful pancreas function.
It is thought that simultaneous kidney-pancreas transplantation can reduce the incidence and progression of diabetic nephropathy in the transplanted kidney compared to kidney transplantation alone in a diabetic patient.
Diabetic retinopathy improves after 3 years of functioning SPK compared to KTA.
Diabetic neuropathy by clinical assessment improves after pancreas transplant alone.
Simultaneous kidney-pancreas transplant patients have higher mortality risk for the first few months post transplantation compared to living kidney transplant patients, however, the risk is equal thereafter and even gets better in patients with functional pancreas at 1 year posttransplant.
More surgical complications are observed post SPK compared to KTA alone and tend to be more likely to increase mortality. These complications are related to the pancreas surgery, which is technically more challenging than kidney transplantation.

Indications for Combined Liver and Kidney Transplantation

The indications for transplanting a kidney with a liver in a patient with cirrhosis requiring a liver transplant are not well defined currently.
Patients requiring a liver transplant that have advanced renal failure that is deemed not likely to recover should get a simultaneous liver and kidney transplant.
Ideally assessment of chronic changes in a kidney should be assessed by kidney biopsy, however, this is frequently not feasible in a patient with cirrhosis due to coagulopathy.
Cirrhotic patients with advanced chronic histologic kidney changes are not likely to recover renal function with liver transplant alone.

Cirrhotic patients with decompensated cirrhosis (with ascites most frequently) may have renal dysfunction that is due to hepatorenal syndrome (HRS) physiology, reduced effective circulation, or other acute insults that can cause ATN.

TABLE 31-1 MINIMUM CRITERIA FOR LISTING FOR LIVER AND KIDNEY TRANSPLANT

If the candidate’s transplant nephrologist confirms a diagnosis of:	Then the transplant program must document in the candidate’s medical record:
Chronic kidney disease (CKD) with a measured or calculated glomerular filtration rate (GFR) less than or equal to 60 mL/min for greater than 90 consecutive days	At least one of the following: That the candidate has begun regularly administered dialysis as ESRD patient. That the candidate’s most recent measured or calculated creatinine clearance (CrCl) or GFR is less than or equal to 35 mL/min at the time of registration on the kidney waiting list.
Sustained acute kidney injury	At least one of the following: That the candidate has been on dialysis for at least 6 consecutive weeks. That the candidate has a measured or calculated CrCl or GFR less than or equal to 25 mL/min for at least 6 consecutive weeks.
Metabolic disease	A diagnosis of at least one of the following: Hyperoxaluria Atypical HUS from mutations in factor H and possibly factor I Familial nonneuropathic systemic amyloid Methylmalonic aciduria

HRS, hemodynamic insults, and ATN causing renal failure secondary decompensated liver cirrhosis usually reverse after successful liver transplant alone.
ESRD caused by a metabolic disease of the liver is also an indication for simultaneous liver and kidney transplantation.
The Organ Procurement and Transplantation Network (OPTN) has proposed the following minimum criteria for simultaneous liver and kidney transplantation (Table 31-1).